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PART III

What Genes Are and What They Do

CHAPTER

Anatomy and Function of a Gene: Dissection Through Mutation

OUTLINE
 3.1 Mutations: Primary Tools of Genetic Analysis  3.2 What Mutations Tell Us About Gene Function  3.4 Examples found in eukaryotic gene regulation lecture

1

Types of mutations in the coding sequence of genes

Fig. 8.28a
Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 8 2

4th edition. Permission required to reproduce or display Hartwell et al.g. Chapter 8 3 . aspartic acid [(-)charged]  alanine (uncharged) Copyright © The McGraw-Hill Companies.Mutations in the coding sequence of a gene can alter the gene product Missense mutations replace one amino acid with another • Conservative – chemical properties of mutant amino acid are similar to the original amino acid  e.g. Inc.. aspartic acid [(-)charged]  glutamic acid [(-)charged] • Nonconservative – chemical properties of mutant amino acid are different from original amino acid  e.

or UAA) Frameshift mutations result from insertion or deletion of nucleotides with the coding region  No frameshift if multiples of three are inserted or deleted Silent mutations do not alter the amino acid sequence  Degenerate genetic code – most amino acids have >1 codon Copyright © The McGraw-Hill Companies. Permission required to reproduce or display Hartwell et al. 4th edition.Mutations in the coding sequence of a gene can alter the gene product (cont) Nonsense mutations change codon that encodes an amino acid to a stop codon (UGA.. UAG. Chapter 8 4 . Inc.

Chapter 8 5 .32a Copyright © The McGraw-Hill Companies.A nonsense mutation in a protein-coding gene creates a truncated. nonfunctional protein Fig 8. Permission required to reproduce or display Hartwell et al. 4th edition.. Inc.

Nonsense suppression A second. Chapter 8 6 .. 4th edition. Permission required to reproduce or display Hartwell et al.32b Copyright © The McGraw-Hill Companies. Inc. nonsense suppressing mutation in the anticodon of a tRNA gene allows production of a (mutant) full-length polypeptide Fig 8.

c Copyright © The McGraw-Hill Companies.. 4th ed.Mutations classified by their effect on DNA Fig..2a . Permission required to reproduce or display Hartwell et al. Inc. 7. Chapter 7 7 .

Mutations classified by their effect on DNA (cont) Fig. Permission required to reproduce or display Hartwell et al.2d Copyright © The McGraw-Hill Companies.. 7. Inc.. Chapter 7 8 . 4th ed.

Inc. Permission required to reproduce or display Hartwell et al.Mutations classified by their effect on DNA (cont) Fig. 4th ed... 7. Chapter 7 9 .2e Copyright © The McGraw-Hill Companies.

How natural processes can change the information stored in DNA Depurination • 1000/hr in every cell Deamination of C • C changed to U • Normal C-G  A-T after replication Fig. 7.. 4th ed. b Copyright © The McGraw-Hill Companies.. Chapter 7 10 .6a. Inc. Permission required to reproduce or display Hartwell et al.

Chapter 7 11 . Permission required to reproduce or display Hartwell et al. 4th ed. 7. Inc.. d Copyright © The McGraw-Hill Companies.6c..How natural processes can change the information stored in DNA (cont) X-rays break the sugar − phosphate backbone of DNA Ultraviolet (UV) light causes adjacent thymines to form abnormal covalent bonds (thymine dimers) Fig.

g. 4th ed. Chapter 7 12 ..How natural processes can change the information stored in DNA (cont) Irradiation causes formation of free radicals (e. reactive oxygen) that can alter individual bases • 8-oxodG mispairs with A • Normal G-C  mutant T-A after replication Fig. Permission required to reproduce or display Hartwell et al. Inc.6e Copyright © The McGraw-Hill Companies.. 7.

Chapter 7 13 .Mistakes during DNA replication Incorporation of incorrect bases by DNA polymerase is exceedingly rare (< 10-9 in bacteria and humans) Two ways that replication machinery minimizes mistakes • Proofreading function of DNA polymerase (Fig 7. Inc.. 4th ed..7)  3'-to-5' exonuclease recognizes and excises mismatches • Methyl-directed mismatch repair (later in this chapter)  Corrects errors in newly replicated DNA Copyright © The McGraw-Hill Companies. Permission required to reproduce or display Hartwell et al.

. 7. Permission required to reproduce or display Hartwell et al.7 Copyright © The McGraw-Hill Companies. Chapter 7 14 . 4th ed. Inc.DNA polymerase’s proofreading function Mispaired base is recognized and excised by 3'-to-5' exonuclease of DNA polymerase Improves fidelity of replication 100-fold Fig..

Permission required to reproduce or display Hartwell et al. Chapter 7 15 .Rates of spontaneous mutation Rates of recessive forward mutations at five coat color genes in mice  11 mutations per gene every 106 gametes Mutation rates in other organisms  2 – 12 mutations per gene every 106 gametes Fig.3b Copyright © The McGraw-Hill Companies.. 4th ed. Inc. 7..

4th ed.Different genes. Inc. different mutation rates Mutation rates are <10-9 to >10-3 per gene per gamete • Differences in gene size • Susceptibility of particular genes to various mutagenic mechanisms Average mutation rate in gamete-producing eukaryotes is higher than that of prokaryotes • Many cell divisions take place between zygote formation and meiosis in germ cells  More chance to accumulate mutations • Can diploid organisms tolerate more mutations than haploid organisms? Copyright © The McGraw-Hill Companies.. Chapter 7 16 .. Permission required to reproduce or display Hartwell et al.

Permission required to reproduce or display Hartwell et al. Chapter 7 17 ..8a Copyright © The McGraw-Hill Companies.. 7.Unequal crossing-over can occur between homologous chromosomes Pairing between homologs during meiosis can be out of register Unequal crossing-over results in a deletion on one homolog and a duplication on the other homolog Fig. Inc. 4th ed.

. Chapter 7 18 . Inc.. 4th ed. 7.Transposable elements (TEs) move around the genome TEs can "jump" into a gene and disrupt its function Two mechanisms of TE movement (transposition) Fig. Permission required to reproduce or display Hartwell et al.8b Copyright © The McGraw-Hill Companies.

10a Copyright © The McGraw-Hill Companies.. Inc. Permission required to reproduce or display Hartwell et al.How mutagens alter DNA: Chemical action of mutagen Replace a base: Base analogs .chemical structure almost identical to normal base Fig. Chapter 7 19 . 7. 4th ed..

Chapter 7 20 .10b Copyright © The McGraw-Hill Companies. Inc.. 7. 4th ed.How mutagens alter DNA: Chemical action of mutagen Alter base structure and properties: Hydroxylating agents add an –OH group Fig. Permission required to reproduce or display Hartwell et al..

. 4th ed.How mutagens alter DNA: Chemical action of mutagen (cont) Alter base structure and properties (cont): Alkylating agents add ethyl or methyl groups Fig. 7.. Chapter 7 21 .10b Copyright © The McGraw-Hill Companies. Inc. Permission required to reproduce or display Hartwell et al.

Inc. Permission required to reproduce or display Hartwell et al.. 4th ed.10b Copyright © The McGraw-Hill Companies.. Chapter 7 22 . 7.How mutagens alter DNA: Chemical action of mutagen (cont) Alter base structure and properties (cont): Deaminating agents remove amine (-NH2) groups Fig.

) Insert between bases: Intercalating agents Fig. Chapter 7 23 . 4th ed.10c Copyright © The McGraw-Hill Companies.. Inc. 7..How mutagens alter DNA: Chemical action of mutagen (cont. Permission required to reproduce or display Hartwell et al.

Permission required to reproduce or display Hartwell et al.Mutations outside the coding sequence can disrupt gene expression Fig. 8. Inc.. 4th edition. Chapter 8 24 .28b Copyright © The McGraw-Hill Companies.

. 4th edition.2 Copyright © The McGraw-Hill Companies. Inc. Permission required to reproduce or display Hartwell et al.Mutations classified by their effects on protein function Table 8. Chapter 8 25 .

11) • Nucleotide excision repair (Fig 7.13) Copyright © The McGraw-Hill Companies.DNA repair mechanisms that are very accurate Reversal of DNA base alterations • Alkyltransferase – removes alkyl groups • Photolyase – splits covalent bond of thymine dimers Homology-dependent repair of damaged bases or nucleotides • Base excision repair (Fig 7. Chapter 7 26 . Permission required to reproduce or display Hartwell et al.. 4th ed. Inc.12) Correction of DNA replication errors • Methyl-directed mismatch repair (Fig 7..

Chapter 7 27 ...11 Copyright © The McGraw-Hill Companies. 4th ed. Permission required to reproduce or display Hartwell et al. 7.Base excision repair removes damaged bases Different glycosylases cleave specific damaged bases Particularly important for removing uracil (created by cytosine deamination) from DNA Fig. Inc.

12 Copyright © The McGraw-Hill Companies. 4th ed. 7. Permission required to reproduce or display Hartwell et al.Nucleotide excision repair corrects damaged nucleotides UvrA – UvrB complex scans for distortions to double helix (e. thymine dimers) UvrB – UvrC complex nicks the damaged DNA  4 nt to one side of damage  7 nt to the other side of damage Fig. Inc... Chapter 7 28 .g.

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